Generation of T cell memory is a critical component of protective immunity, yet the cellular and molecular requirements involved in establishing functional T cell memory are poorly understood. While memory T cells normally arise following priming of naive T cells with foreign antigen, a distinct pathway can also generate functional memory T cells - as a consequence of homeostatic proliferation in a lymphopenic environment. Study of memory T cells produced by homeostatic proliferation ("HP memory" cells) is relevant to understanding the essential requirements for memory T cell differentiation, and also for assessing the relevance of this alternative pathway in establishing protective immunity in immunocompromized individuals. Using mouse models, we recently showed that both "conventional memory" T cells (i.e. those generated through priming) and HP memory CDS T cells offer similar protective immunity against a pathogen. Also like conventional memory CDS T cells, the function of HP memory CDS T cells depends on them receiving CD4 T cell "help" during their generation. However, the exact nature of this CD4 help and the basis for the defective response of "helpless" memory CDS cells (i.e. those generated without CD4 T cells) is still unclear. Furthermore, both the role of CD4 cells and the characteristics of helpless memory CDS cells appears to be different under HP versus conventional memory pathways. Our main goals in this proposal are to 1) establish the nature of CD4 "help" during generation of functional HP memory CDS T cells; 2) determine the basis for defective function of helpless HP memory CDS T cells and 3) to extend these studies into looking at the properties of HP memory cells which arise during physiological conditions.